Azo- and butadiyne-linked 5,10-diarylporphyrins

Porphyrins are one of Nature’s essential building blocks that play an important role in several biological systems including oxygen transport, photosynthesis, and enzymes. Their capacity to absorb visible light, facilitate oxidation and reduction, and act as energy- and electron-transfer agents, in particular when several are held closely together, is of interest to chemists who seek to mimic Nature and to make and use these compounds in order to synthesise novel advanced materials. During this project 26 new 5,10-diarylsubstituted porphyrin monomers, 10 dimers, and 1 tetramer were synthesised. The spectroscopic and structural properties of these compounds were investigated using 1D/2D 1H NMR, UV/visible, ATR-IR and Raman spectroscopy, mass spectrometry, X-ray crystallography, electrochemistry and gel permeation chromatography. Nitration, amination, bromination and alkynylation of only one as well as both of the meso positions of the porphyrin monomers have resulted in the expansion of the synthetic possibilities for the 5,10-diarylsubstituted porphyrins. The development of these new porphyrin monomers has led to the successful synthesis of new azo- and butadiyne-linked dimers. The functionalisation of these compounds was investigated, in particular nitration, amination, and bromination. The synthesised dimers containing the azo bridge have absorption spectra that show a large split in the Soret bands and intense Q-bands that have been significantly redshifted. The butadiyne dimers also have intense, red-shifted Q-bands but smaller Soret band splittings. Crystal structures of two new azoporphyrins have been acquired and compared to the azoporphyrin previously synthesised from 5,10,15- triarylsubstituted porphyrin monomers. A completely new cyclic porphyrin oligomer (CPO) was synthesised comprising four porphyrin monomers linked by azo and butadiyne bridges. This is the first cyclic tetramer that has both the azo and butadiyne linking groups. The absorption spectrum of the tetramer exhibits a large Soret split making it more similar to the azo- dimers than the butadiyne-linked dimers. The spectroscopic characteristics of the synthesised tetramer have been compared to the characteristics of other cyclic porphyrin tetramers. The collected data indicate that the new synthesised cyclic tetramer has a more efficient ð-overlap and a better ground state electronic communication between the porphyrin rings.

NADPH oxidases as regulators of tumor angiogenesis : current and emerging concepts

Significance Reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and peroxynitrite are generated ubiquitously by all mammalian cells and have been understood for many decades as inflicting cell damage and as causing cancer by oxidation and nitration of macromolecules, including DNA, RNA, proteins, and lipids. Recent Advances A current concept suggests that ROS can also promote cell signaling pathways triggered by growth factors and transcription factors that ultimately regulate cell proliferation, differentiation, and apoptosis, all of which are important hallmarks of tumor cell proliferation and angiogenesis. Moreover, an emerging concept indicates that ROS regulate the functions of immune cells that infiltrate the tumor environment and stimulate angiogenesis, such as macrophages and specific regulatory T cells. Critical Issues In this article, we highlight that the NADPH oxidase family of ROS-generating enzymes are the key sources of ROS and, thus, play an important role in redox signaling within tumor, endothelial, and immune cells thereby promoting tumor angiogenesis. Future Directions Knowledge of these intricate ROS signaling pathways and identification of the culprit NADPH oxidases is likely to reveal novel therapeutic opportunities to prevent angiogenesis that occurs during cancer and which is responsible for the revascularization after current antiangiogenic treatment.

Chemical aspects of the hypergolic preignition reactions of some hybrid hypergols

A new class of solid compounds, viz., bisthiocarbonohydrazones and thiosemicarbazones, have been found to be hypergolic with fuming nitric acid. The observed ignition delays of these hypergols have been compared with those of the monothiocarbonohydrazones-nitric acid systems and explained in terms of the chemical reactions-neutralization, oxidation, and nitration-occurring in the preignition stage. p-Nitrobenzoic acid, benzoic acid, benzaldehyde, sulfur trioxide, nitrogen dioxide, and nitrogen have been isolated as preignition reaction intermediates in the mono- and bisbenzaldehydethiocarbonohydrazone-nitric acid systems. A scheme of reactions occurring in the preignition stage is proposed based on the formation of these products.

Synthesis and Antioxidant Activity of Peptide-Based Ebselen Analogues

A series of di- and tripeptide-based ebselen analogues has been synthesized. The compounds were characterized by H-1, C-13, and Se-77 NMR spectroscopy and mass spectral techniques. The glutathione peroxidase (GPx)-like antioxidant activity has been studied by using H2O2, tert-butyl hydroperoxide (tBuOOH), and cumene hydroperoxide (Cum-OOH) as substrates, and glutathione (GSH) as a co-substrate. Although all the peptide-based compounds have a selenazole ring similar to that of ebselen, the GPx activity of these compounds highly depends on the nature of the peptide moiety attached to the nitrogen atom of the selenazole ring. It was observed that the introduction of a phenylalanine (Phe) amino acid residue in the N-terminal reduces the activity in all three peroxide systems. On the other hand, the introduction of aliphatic amino acid residues such as valine (Val) significantly enhances the GPx activity of the ebselen analogues. The difference in the catalytic activity of dipeptide-based ebselen derivatives can be ascribed mainly to the change in the reactivity of these compounds toward GSH and peroxide. Although the presence of the Val-Ala-CO2Me moiety facilitates the formation of a catalytically active selenol species, the reaction of ebselen analogues that has a Phe-Ile-CO2Me residue with GSH does not generate the corresponding selenol. To understand the antioxidant activity of the peptide-based ebselen analogues in the absence of GSH, these compounds were studied for their ability to inhibit peroxynitrite (PN)-mediated nitration of bovine serum albumin (BSA) and oxidation of dihydrorhodamine 123. In contrast to the GPx activity, the PN-scavenging activity of the Phe-based peptide analogues was found to be comparable to that of the Val-based compounds. However, the introduction of an additional Phe residue to the ebselen analogue that had a Val-Ala dipeptide significantly reduced the potency of the parent compound in PN-mediated nitration.

Structural characterization of angiotensin I-converting enzyme in complex with a selenium analogue of captopril

Human somatic angiotensin I-converting enzyme (ACE), a zinc-dependent dipeptidyl carboxypeptidase, is central to the regulation of the renin-angiotensin aldosterone system. It is a well-known target for combating hypertension and related cardiovascular diseases. In a recent study by Bhuyan and Mugesh [Org. Biomol. Chem. (2011) 9, 1356-1365], it was shown that the selenium analogues of captopril (a well-known clinical inhibitor of ACE) not only inhibit ACE, but also protect against peroxynitrite-mediated nitration of peptides and proteins. Here, we report the crystal structures of human testis ACE (tACE) and a homologue of ACE, known as AnCE, from Drosophila melanogaster in complex with the most promising selenium analogue of captopril (SeCap) determined at 2.4 and 2.35 angstrom resolution, respectively. The inhibitor binds at the active site of tACE and AnCE in an analogous fashion to that observed for captopril and provide the first examples of a protein-selenolate interaction. These new structures of tACE-SeCap and AnCE-SeCap inhibitor complexes presented here provide important information for further exploration of zinc coordinating selenium-based ACE inhibitor pharmacophores with significant antioxidant activity.

Spirodiazaselenuranes: synthesis, structure and antioxidant activity

In this paper, the synthesis, characterization and glutathione peroxidase and peroxynitrite scavenging activities of a series of stable spirodiazaselenuranes are described. The spiro compounds were synthesized in good yields by oxidative cyclization of diaryl selenides bearing amide moieties. All the selenides and spiro derivatives were characterized by H-1, C-13 and Se-77 NMR spectroscopy, mass spectral techniques and the structures of some of the spirodiazaselenuranes were confirmed by single crystal X-ray crystallography. The structures reveal that the selenium atom occupies the center of a distorted trigonal bipyramid core with two nitrogen atoms occupying the apical positions and two carbon atoms and the selenium lone pair occupying the equatorial positions. Mechanistic investigations indicate that the spirocyclization occurs via the formation of selenoxide intermediates. The new compounds were evaluated for their glutathione peroxidase (GPx) mimetic activity by using H2O2 as a substrate and glutathione (GSH) as a co-substrate. It was found that the substituents attached to the nitrogen atom of the selenazole ring have a significant effect on the GPx activity. While the introduction of electron withdrawing groups such as -Cl, -Br etc. to the phenyl ring decreases the activity, the introduction of electron donating groups such as -OH, -OMe significantly enhances the GPx activity of both diaryl selenides and spirodiazaselenuranes. In addition to GPx activity, the selenides and spiro derivatives were studied for their ability to inhibit peroxynitrite (PN)-mediated nitration of bovine serum albumin (BSA) and oxidation of dihydrorhodamine 123. These studies indicate that the diarylselenides effectively inhibit the PN-mediated nitration and oxidation reactions by reacting with PN to produce the corresponding spirodiazaselenuranes.

Substituent Effects on the Stability and Antioxidant Activity of Spirodiazaselenuranes

Spirodiazaselenuranes are structurally interesting compounds and the stability of these compounds depends highly on the nature of the substituents attached to the nitrogen atoms. Aromatic substituents are known to play important roles in stabilizing the Se-N bonds in spiro compounds. In this study, several spirodiazaselenuranes are synthesized by introducing benzylic and aliphatic substituents to understand their effect on the stability of the Se-N bonds and the antioxidant activity. Replacement of phenyl substituent by benzyl/alkyl groups significantly reduces the stability of the spirodiazaselenuranes and slows down the oxidative cyclization process. The selenium centre in the spiro compounds undergoes further oxidation to produce the corresponding selenurane oxides, which are stable at room temperature. Comparison of the glutathione peroxidase (GPx) mimetic activity of the compounds showed that the diaryl selenides having heterocyclic rings are significantly more active due to the facile oxidation of the selenium centre. However, the activity is reduced significantly for compounds having aliphatic substituents. In addition to GPx activity, the compounds also inhibit peroxynitrite-mediated nitration and oxidation reaction of protein and small molecules, respectively. The experimental observations suggest that the antioxidant activity is increased considerably upon substitution of the aromatic group with the benzylic/aliphatic substituents on the nitrogen atoms.

Síntese, caracterização e avaliação de materiais poliméricos com propriedades bactericidas

Nesta dissertação, foram preparados materiais poliméricos com atividade bactericida a partir de copolímeros de estireno (Sty) e divinilbenzeno (DVB) e de celulose bacteriana. Três copolímeros à base de Sty e DVB foram sintetizados através da técnica de polimerização em suspensão aquosa. Os copolímeros foram preparados com diferentes estruturas porosas, por meio da variação da composição do sistema diluente. Um copolímero comercial macrorreticulado, Amberlite XAD4, de elevada área superficial, também foi usado neste estudo com o objetivo de comparar sua estrutura polimérica e seu desempenho com o dos copolímeros sintetizados. Os copolímeros de Sty-DVB foram caracterizados por meio da densidade aparente, área específica, diâmetro médio de poros, volume de poros, microscopias ótica e eletrônica de varredura, grau de inchamento, espectrometria de infravermelho com transformada de Fourier (FTIR), análise termogravimétrica e análise elementar. Os copolímeros de Sty-DVB foram modificados quimicamente através da reação de nitração, seguida da reação de redução do grupo nitro a amino e posterior reação de diazotação e hidrólise do grupo sal de diazônio. Os copolímeros modificados contendo os grupos NH2 e OH foram utilizados como suporte para a ancoragem das nanopartículas de prata. As partículas de prata foram obtidas pela redução dos íons Ag+ empregando-se cloridrato de hidroxilamina como redutor e PVP como protetor de colóide. O teor de prata impregnada foi determinado pelo método volumétrico. A celulose bacteriana (BC) foi empregada como uma matriz para impregnação de nanopartículas de prata. Membranas de BC foram impregnadas com solução aquosa de AgNO3, a seguir foi realizada a redução dos íons Ag+ com três diferentes agentes redutores (hidrazina, hidroxilamina e ácido ascórbico) empregando ou não protetor de colóide (PVP ou gelatina). As membranas de BC/Ag0 obtidas foram caracterizadas por difração de raios-X, análise termogravimétrica e microscopia eletrônica de varredura. A capacidade bactericida dos copolímeros de Sty-DVB, dos copolímeros funcionalizados e impregnados com prata e das membranas de BC/Ag0 foi avaliada através do método da contagem em placa contra suspensões de Escherichia coli, em diferentes concentrações (103 a 107 células/mL). Foi observado que os copolímeros de origem e os copolímeros modificados contendo os grupos NO2 e NH2 não apresentaram atividade bactericida contra suspensões de E. coli em nenhuma concentração. Por outro lado, os copolímeros modificados contendo o grupo OH apresentaram alguma atividade bactericida, embora abaixo do esperado devido à baixa incorporação de hidroxilas fenólicas. Os copolímeros modificados impregnados com Ag apresentaram maior ação bactericida do que os copolímeros modificados, o que comprova que a ação bactericida é devida às partículas de prata ancoradas nos copolímeros. Os copolímeros modificados contendo o grupo OH impregnados com Ag mesmo possuindo menores teores de prata apresentaram maior ação bactericida do que os copolímeros modificados contendo o grupo NH2 impregnados com Ag. A maior ação bactericida pode ser atribuída à combinação da atividade bactericida das partículas de prata com a atividade dos grupos hidroxilas fenólicas mesmo que estes grupos estejam pouco incorporados nos copolímeros. Os compósitos de BC/Ag0 exibiram atividade bactericida contra E. coli que foi atribuída à ação das nanoparticulas de prata obtidas quando foi empregada a hidroxilamina como agente redutor e a gelatina como protetor de colóide

亚硝化—厌氧氨氧化处理猪场废水研究

猪场废水COD浓度高、氨氮浓度高、悬浮物浓度高，已成为农村面源污染的主要来源，并严重威胁到农村饮用水安全。猪场废水氨氮浓度高、处理难度大，如何采用经济高效的方法，去除氨氮使其达到排放标准，一直是猪场废水处理中面临的重要难题。 厌氧氨氧化是近年受到国内外水处理研究者广泛关注的新型生物脱氮技术，具有不需要外加有机碳源、节省供氧量、降低能耗等优点。虽然国内外研究者对厌氧氨氧化过程的脱氮机理、厌氧氨氧化菌的生理生化特性等进行了多方面的研究，但已有的报道大多以模拟废水为研究对象，以猪场废水为研究对象的报道，在国内外文献中极少有报导。 本论文以猪场废水为主要研究对象，考察了猪场废水的亚硝化过程、厌氧氨氧化的启动过程，并对亚硝化和厌氧氨氧化联合用于猪场废水脱氮进行了探索。 1．论文首先研究了猪场废水的亚硝化过程，考察了废水水质和主要运行条件对亚硝化过程的影响。实验表明：（1）亚硝化阶段反应时间为8到10h时，出水中氨氮和亚硝酸盐浓度比可达到1：1～1：1.23，满足厌氧氨氧化反应对二者比例的要求；达到前述要求时，氨氮去除率达到58.3～65.6 %，亚硝化率在整个过程均保持在97 %以上，COD去除率在59.2～68.6 %；（2）曝气量（溶解氧）对亚硝化过程影响显著，随着曝气量增大，达到厌氧氨氧化要求的氨氮与亚硝酸盐氮浓度比例所需水力停留时间τ越短，pH出现明显下降的时间越短；（3）τ对应的pH在7.8～8.1之间，无需进行pH调节即可满足厌氧氨氧化反应对pH的要求；（4）氨氮和COD降解过程遵循一级反应动力学，氨氮和COD降解的速率常数分别为0.0656～0.0724 1/h和0.0491～0.0664 1/h。 2．在进行亚硝化过程研究的同时，以模拟废水为试验对象，进行厌氧氨氧化启动研究。以反硝化污泥和养殖厂储水池厌氧底泥的混合污泥作为接种污泥，历时大约100天，培育出具有厌氧氨氧化活性的污泥，氨氮和亚硝酸盐氮最高进水浓度分别为223.8 mg/L和171.4 mg/L，去除率最高分别达48%和41.5%，此时二者消耗比例为1.33：1。 3．在猪场废水的亚硝化研究完成和厌氧氨氧化过程初步启动成功后，在模拟废水中逐步加入猪场废水的亚硝化处理出水，逐步实现亚硝化和厌氧氨氧化的组合。亚硝化出水添加到厌氧反应器后，厌氧氨氧化反应仍可继续进行，且去除效率逐步提高。研究发现添加的亚硝化出水中携带的亚硝化细菌在厌氧氨氧化菌膜外层生长并累积，增加了厌氧氨氧化反应基质的传质阻力，妨碍了厌氧氨氧化效率的提高。 4．亚硝化－厌氧氨氧化实际工程应用探索中，生物接触氧化池可在有效去除废水中的有机物的同时实现亚硝化，出水中氨氮和亚硝酸盐比例平均为1.10，可满足后续厌氧氨氧化的要求；在适宜的进水浓度和温度下，ABR池出现了厌氧氨氧化启动的迹象；研究同时发现，水质的波动和气温的变化是工程中影响厌氧氨氧化菌活性的重要因素。 论文的主要创新点在于：（1）以猪场废水为研究对象，以实现厌氧氨氧化为目标，对亚硝化过程进行了比较详细的考察，获得了亚硝化出水满足厌氧氨氧化要求的工艺条件，通过对其COD和氨氮降解过程的考察，得出亚硝化阶段COD降解和氨氮去除的动力学模型；（2）对亚硝化－厌氧氨氧化处理猪场废水进行了探索，确立了影响其污染物去除率稳定的重要因素。 论文的上述研究成果，为厌氧氨氧化技术的实用性研究提供理论依据。 Piggery wastewater, which is characterized by high concentration of COD、ammonium and suspend substance, has become a most important source of non-point source pollution and also severely threats drinking water security in rural area. How to discharge piggery wastewater with the ammonium concentration meeting standard by economical and effective method? This is the most urgent problem in piggery wastewater treatment. As a new biological nitrogen removal technology, Anammox process has been paid more and more attention by researchers all over the world. Anammox has advantages of no need of organic carbon addition, low oxygen consumption and energy consumption. Plenty of investigations have been carried out to the mechanism, physiological and biochemical characteristic of bacteria about Anammox. Most of researches focused on synthetic wastewater, there is rare report about its application in piggery wastewater. In this paper，experimental studies were performed to investigate Sharon process in treatment of piggery wastewater，the start up process of Annammox using synthetic wastewater were studied, the feasibility of applying Sharon-Anammox process in the nitrogen removal of piggery wastewater was evaluated. 1. Sharon process of piggery wastewater was firstly investigated to analyze the effects of water quality and main running parameters, which meet the NH4+-N to NO2--N ratio requirement of successive Anammox. Results showed: (1)During Sharon Process，after 8～10 hours’ reaction the NH4+-N to NO2--N ratio in effluent reached 1:1.0～1:1.23, when the removal percentage of NH4+-N was 58.3～65.6 %, a semi-nitration rate of above 97 % was achieved during the process; meanwhile 59.2～68.6 % of the COD was also removed. (2)The aeration rate（oxygen） had obvious effect on the hydraulic retention time(τ) which met the NH4+-N to NO2--N ratio requirement of Anammox. As aeration rate increased, the hydraulic retention time(τ) was shortened. (3) The pH corresponding to τ was between 7.8 and 8.1, thus it needed no artificial adjustment. (4) The reduction of ammonia and COD followed the first-order reaction kinetics. The velocity constants of ammonia and COD were 0.0656～0.0724 1/h and 0.0491～0.0664 1/h, respectively. 2. The startup of Anammox process using the artificial wastewater was performed simultaneously with Sharon. The aim was to investigate the running parameters of Anammox and make foundation for the combination stage. By using the mixture of denitrifying sludge and anaerobic sludge in tank of the breeding factory, sludge of Anammox activity was cultivated in UASB after 100 days. The removal percentage of NH4+-N and NO2-N were up to 48% and 41.5%, respectively, when the NH4+-N and NO2-N influent concentration were 223.8 mg/L and 171.4 mg/L, respectively, the NH4+-N and NO2-N removal rate was 1.33:1. 3. After investigation of Sharon and startup of Anammox, effluent of Sharon process was added into the synthetic wastewater to combine Sharon and Anammox step by step. It took some time after the addition of Sharon effluent that Anammox reaction continued and the removal rate kept increasing. It indicated that nitrifying bacteria were carried by the Sharon effluent cumulated in the outer layer of Anammox. This enhanced transfer resistance of Anammox reaction and the increasing removal rate was restrained. 4. In the bio-contact oxidation pond of practical project, Sharon process were carried out successfully and organic compounds were removed effectively. An average NO2-N/ NH4+-N rate of 1:1.0 was achieved in the effluent, which met the requirement of successive Anammox. Under condition of suitable influent concentration and temperature, there was evidence that Anammox could start up in ABR. The variety of wastewater and temperature had great affects on Anammox activity in practical engineering. Innovation of this paper: (1) The Sharon process for treating piggery wastewater was discussed in details. Technological parameters that met requirement of Anammox were obtained. The dynamic models of COD and ammonium removal in the process were educed. (2) Sharon-Ananmmox for treatment of piggery wastewater was investigated, and the primary influencing factors was studied. This paper could be a theoretical consult for research of Anammox utility.

Synthesis and gas transport property of polyimide from 2,2 '-disubstituted biphenyltetracarboxylic dianhydrides (BPDA)

A series of dianhydride monomers, 2,2'-disubstituted-4,4',5,5'-biphenyltetracarboxylic dianhydride (substituents = phenoxy, p-methylphenoxy, p-tert-butylphenoxy, nitro, and methoxy) were synthesized by the nitration of an N-methyl protected 3,3',4,4'-biphenyttetracarboxylic dianhydride (BPDA) and subsequent aromatic nucleophilic substitutions with aroxides (NaOAr) or methoxide. These dianhydrides were polymerized with various aromatic diamines in refluxing m-cresol containing isoquinoline to afford a series of aromatic polyintides. The effects of varying 2,2'-substituents of the dianhydride (BPDA) moiety on the properties of polyimides were investigated. It was found that polyimides from the dianhydrides containing phenoxy, p-methylphenoxy, and p-tert-butylphenoxy side groups possessed excellent solubility and film forming capability whereas polyimides from 2,2'-dinitro-BPDA and 2,2'-dimethoxy-BPDA were less soluble in organic solvent. The soluble polymers formed flexible, tough and transparent films. The films had a tensile strength, elongation at break, and Young's modulus in the ranges 102-168 MPa, 8-21%, 2.02-2.38 GPa, respectively. The polymer gas permeability coefficients (P) and ideal selectivities for N-2, O-2, CO2 and CH4 were determined for the -OAr substituted polyimides. The oxygen permeability coefficient (P-O2) and permselectivity of oxygen to nitrogen (PO2/N-2) of the films were in the ranges 3.4-11.3 barrer and 3.8-4.6, respectively.

Mitochondrial plasticity in pathophysiological conditions

Both skeletal and cardiac muscles daily burn tremendous amounts of ATP to meet the energy requirements for contraction. So, it is not surprising that the maintenance of mitochondrial morphology, number, distribution and functionality in striated muscle are important for muscle homeostasis. In these tissues mitochondria present the added dimension of two populations, the intermyofibrillar (IMF) and the subsarcolemmal (SS) mitochondria, being IMF the most abundant one. In the present thesis, the molecular mechanisms harboured in mitochondria of striated muscles were studied using animal models, to better comprehend the role of mitochondrial plasticity in several pathophysiological conditions such as aging, diabetes mellitus and bladder cancer. The comparative analysis of IMF and SS populations isolated from heart evidenced a higher respiratory chain activity of mitochondria interspersed in the contractile apparatus. The higher susceptible of SS respiratory chain complexes subunits to carbonylation, but not to nitration, seems to justify the lower respiratory chain activity observed in this mitochondrial population. Our results showed that in heart from aged mice there is an accumulation of dysfunctional mitochondria. The age-related decrease of oxidative phosphorylation activity seems to be justified, at least partially, by the increased proneness of mitochondrial proteins as OXPHOS subunits and MnSOD to oxidative modifications. Moreover, a sedentary lifestyle seems to worsen the functional consequences of aging in heart by increasing mitochondrial proteins susceptibility to nitration. In skeletal muscle from rats with type 1 diabetes mellitus induced by streptozotocin administration, we verified the accumulation of dysfunctional mitochondria due, at least in part, to the impairment of PQC system. Indeed, the decreased activity of AAA proteases was accompanied by the accumulation of oxidatively modified mitochondrial proteins with impact in respiratory chain activity. The diminishing of mitochondria activity also underlies cancer-induced muscle wasting. Indeed, using a rat model of chemically induced urothelial carcinoma we verified that the loss of gastrocnemius mass was related to mitochondrial dysfunction due to, at least partially, the down-regulation of PQC system involving the mitochondrial proteases paraplegin and Lon. PQC impairment resulted in the accumulation of oxidatively modified mitochondrial proteins. In overall, regardless the pathophysiological stimuli that promote mitochondrial alterations, there are similarities in the pattern of disease-related mitochondrial plasticity. The diminished capacity for ATP production in striated muscle seems to be due to increased oxidative damage of mitochondrial proteins, namely subunits of respiratory chain complexes, metabolic proteins and MnSOD. Our data highlighted, for the first time, the impact of mitochondrial PQC system impairment in the accumulation of oxidized proteins, exacerbating the dysfunction of this organelle in striated muscle in several pathophysiological conditions.

Limited capacity for ammonia removal by brain in chronic liver failure: potential role of nitric oxide.

Chronic liver failure leads to hyperammonemia and consequently increased brain ammonia concentrations, resulting in hepatic encephalopathy. When the liver fails to regulate ammonia concentrations, the brain, devoid of a urea cycle, relies solely on the amidation of glutamate to glutamine through glutamine synthetase, to efficiently clear ammonia. Surprisingly, under hyperammonemic conditions, the brain is not capable of increasing its capacity to remove ammonia, which even decreases in some regions of the brain. This non-induction of glutamine synthetase in astrocytes could result from possible limiting substrates or cofactors for the enzyme, or an indirect effect of ammonia on glutamine synthetase expression. In addition, there is evidence that nitration of the enzyme resulting from exposure to nitric oxide could also be implicated. The present review summarizes these possible factors involved in limiting the increase in capacity of glutamine synthetase in brain, in chronic liver failure.

Studies on catalysis by transition metal promoted sulphated zirconia

The present project was a systematic investigation of the physico-chemical properties and catalytic activity of some transition metal promoted sulphated zirconia systems. The characterisation and catalytic activity results were compared with that of pure Zr02 and simple sulphated zirconia systems. Sulphated zirconia samples were prepared by a controlled impregnation technique. In the case of metal incorporated systems, a single step impregnation was carried out using required amounts of sulphuric acid and metal salt solutions. As a preliminary step, optimisation of calcination temperature and sulphate content was achieved. For further studies, the optimised sulphate loading of 10 ml per gram of hydrous zirconium oxide and a calcination temperature of 700°C was employed. Metal incorporation had a positive influence on the physico-chemical properties. Vapour phase cumene conversion served as a test reaction for acidity. Some industrially important reactions like Friedel-Crafts reaction, phenol hydroxylation, nitration, etc. were selected to test the catalytic activity of the prepared systems.

‘‘catalysis by nano sulfated titania modified by transition metals"

in the present study, we have prepared and evaluated the physical and chemical properties and catalytic activities of transition metal loaded sulfated titania via the sol-gel route. Sol-gel method is widely used for preparing porous materials having controlled properties and leads to the formation of oxide particles in nano range, which are spherical or interconnected to each other. Characterization using various physico-chemical techniques and a detailed study of acidic properties are also carried out. Some reactions of industrial importance such as Friedel-Crafts reaction, fen-butylation of phenol,Beckmann rearrangement of cyclohexanone oxime, nitration of phenol and photochemical degradation of methylene blue have been selected for catalytic activity study in the present venture. The work is organized into eight chapters

A "Trojan horse" strategy to reverse drug-resistance in brain tumors

Los gliomas malignos representan una de las formas más agresivas de los tumores del sistema nervioso central (SNC). De acuerdo con la clasificación de los tumores cerebrales de la Organización Mundial de la Salud (OMS), los astrocitomas han sido categorizados en cuatro grados, determinados por la patología subyacente. Es así como los gliomas malignos (o de alto grado) incluyen el glioma anaplásico (grado III) así como el glioblastoma multiforme (GBM, grado IV),estos últimos los más agresivos con el peor pronóstico (1). El manejo terapéutico de los tumores del SNC se basa en la cirugía, la radioterapia y la quimioterapia, dependiendo de las características del tumor, el estadio clínico y la edad (2),(3), sin embargo ninguno de los tratamientos estándar es completamente seguro y compatible con una calidad de vida aceptable (3), (4). En general, la quimioterapia es la primera opción en los tumores diseminados, como el glioblastoma invasivo y el meduloblastoma de alto riesgo o con metástasis múltiple, pero el pronóstico en estos pacientes es muy pobre (2),(3). Solamente nuevas terapias dirigidas (2) como las terapias anti-angiogénicas (4); o terapias génicas muestran un beneficio real en grupos limitados de pacientes con defectos moleculares específicos conocidos (4). De este modo, se hace necesario el desarrollo de nuevas terapias farmacológicas para atacar los tumores cerebrales. Frente a las terapias los gliomas malignos son con frecuencia quimioresistentes, y esta resistencia parece depender de al menos dos mecanismos: en primer lugar, la pobre penetración de muchas drogas anticáncer a través de la barrera hematoencefálica (BBB: Blood Brain Barrier), la barrera del fluido sangre-cerebroespinal (BCSFB: Blood-cerebrospinal fluid barrier) y la barrera sangre-tumor (BTB: blood-tumor barrier). Dicha resistencia se debe a la interacción de la droga con varios transportadores o bombas de eflujo de droga ABC (ABC: ATP-binding cassette) que se sobre expresan en las células endoteliales o epiteliales de estas barreras. En segundo lugar, estos transportadores de eflujo de drogas ABC propios de las células tumorales confieren un fenotipo conocido como resistencia a multidrogas (MDR: multidrug resistance), el cual es característico de varios tumores sólidos. Este fenotipo también está presente en los tumores del SNC y su papel en gliomas es objeto de investigación (5). Por consiguiente el suministro de medicamentos a través de la BBB es uno de los problemas vitales en los tratamientos de terapia dirigida. Estudios recientes han demostrado que algunas moléculas pequeñas utilizadas en estas terapias son sustratos de la glicoproteína P (Pgp: P-gycoprotein), así como también de otras bombas de eflujo como las proteínas relacionadas con la resistencia a multidrogas (MRPs: multidrug resistance-related proteins (MRPs) o la proteína relacionada con cáncer de seno (BCRP: breast-cancer resistance related protein)) que no permiten que las drogas de este tipo alcancen el tumor (1). Un sustrato de Pgp y BCRP es la DOXOrubicina (DOXO), un fármaco utilizado en la terapia anti cáncer, el cual es muy eficaz para atacar las células del tumor cerebral in vitro, pero con un uso clínico limitado por la poca entrega a través de la barrera hematoencefálica (BBB) y por la resistencia propia de los tumores. Por otra parte las células de BBB y las células del tumor cerebral tienen también proteínas superficiales, como el receptor de la lipoproteína de baja densidad (LDLR), que podría utilizarse como blanco terapéutico en BBB y tumores cerebrales. Es asi como la importancia de este estudio se basa en la generación de estrategias terapéuticas que promuevan el paso de las drogas a través de la barrera hematoencefalica y tumoral, y a su vez, se reconozcan mecanismos celulares que induzcan el incremento en la expresión de los transportadores ABC, de manera que puedan ser utilizados como blancos terapéuticos.Este estudio demostró que el uso de una nueva estrategia basada en el “Caballo de Troya”, donde se combina la droga DOXOrubicina, la cual es introducida dentro de un liposoma, salvaguarda la droga de manera que se evita su reconocimiento por parte de los transportadores ABC tanto de la BBB como de las células del tumor. La construcción del liposoma permitió utilizar el receptor LDLR de las células asegurando la entrada a través de la BBB y hacia las células tumorales a través de un proceso de endocitosis. Este mecanismo fue asociado al uso de estatinas o drogas anticolesterol las cuales favorecieron la expresión de LDLR y disminuyeron la actividad de los transportadores ABC por nitración de los mismos, incrementando la eficiencia de nuestro Caballo de Troya. Por consiguiente demostramos que el uso de una nueva estrategia o formulación denominada ApolipoDOXO más el uso de estatinas favorece la administración de fármacos a través de la BBB, venciendo la resistencia del tumor y reduciendo los efectos colaterales dosis dependiente de la DOXOrubicina. Además esta estrategia del "Caballo de Troya", es un nuevo enfoque terapéutico que puede ser considerado como una nueva estrategia para aumentar la eficacia de diferentes fármacos en varios tumores cerebrales y garantiza una alta eficiencia incluso en un medio hipóxico,característico de las células cancerosas, donde la expresión del transportador Pgp se vió aumentada. Teniendo en cuenta la relación entre algunas vías de señalización reconocidas como moduladores de la actividad de Pgp, este estudio presenta no solo la estrategia del Caballo de Troya, sino también otra propuesta terapéutica relacionada con el uso de Temozolomide más DOXOrubicina. Esta estrategia demostró que el temozolomide logra penetrar la BBB por que interviene en la via de señalización de la Wnt/GSK3/β-catenina, la cual modula la expresión del transportador Pgp. Se demostró que el TMZ disminuye la proteína y el mRNA de Wnt3 permitiendo plantear la hipótesis de que la droga al disminuir la transcripción del gen Wnt3 en células de BBB, incrementa la activación de la vía fosforilando la β-catenina y conduciendo a disminuir la β-catenina nuclear y por tanto su unión al promotor del gen mdr1. Con base en los resultados este estudio permitió el reconocimiento de tres mecanismos básicos relacionados con la expresión de los transportadores ABC y asociados a las estrategias empleadas: el primero fue el uso de las estatinas, el cual condujo a la nitración de los transportadores disminuyendo su actividad por la via del factor de transcripción NFκB; el segundo a partir del uso del temozolomide, el cual metila el gen de Wnt3 reduciendo la actividad de la via de señalización de la la β-catenina, disminuyendo la expresión del transportador Pgp. El tercero consistió en la determinación de la relación entre el eje RhoA/RhoA quinasa como un modulador de la via (no canónica) GSK3/β-catenina. Se demostró que la proteína quinasa RhoA promovió la activación de la proteína PTB1, la cual al fosforilar a GSK3 indujo la fosforilación de la β-catenina, lo cual dio lugar a su destrucción por el proteosoma, evitando su unión al promotor del gen mdr1 y por tanto reduciendo su expresión. En conclusión las estrategias propuestas en este trabajo incrementaron la citotoxicidad de las células tumorales al aumentar la permeabilidad no solo de la barrera hematoencefálica, sino también de la propia barrera tumoral. Igualmente, la estrategia del “Caballo de Troya” podría ser útil para la terapia de otras enfermedades asociadas al sistema nervioso central. Por otra parte estos estudios indican que el reconocimiento de mecanismos asociados a la expresión de los transportadores ABC podría constituir una herramienta clave en el desarrollo de nuevas terapias anticáncer.